WO2019246343A1 - Inhibiteurs de la nadph oxydase, composition pharmaceutique les comprenant et application de ceux-ci - Google Patents

Inhibiteurs de la nadph oxydase, composition pharmaceutique les comprenant et application de ceux-ci Download PDF

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Publication number
WO2019246343A1
WO2019246343A1 PCT/US2019/038140 US2019038140W WO2019246343A1 WO 2019246343 A1 WO2019246343 A1 WO 2019246343A1 US 2019038140 W US2019038140 W US 2019038140W WO 2019246343 A1 WO2019246343 A1 WO 2019246343A1
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compound
alkyl
aryl
heterocyclyl
halogen
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PCT/US2019/038140
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English (en)
Inventor
Syaulan S. YANG
Kuang Yuan Lee
Meng Hsien Liu
Yan-feng JIANG
Yu-Shiou FAN
Chiung Wen Wang
Mei-Chi Hsu
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Taiwanj Pharmaceuticals Co., Ltd.
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Priority to US17/254,565 priority Critical patent/US11661400B2/en
Priority to EP19822444.6A priority patent/EP3810143A4/fr
Priority to CN201980041579.7A priority patent/CN112292131A/zh
Publication of WO2019246343A1 publication Critical patent/WO2019246343A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • ROS Reactive Oxygen Species
  • ROS are a number of reactive molecules and free radicals derived from molecular oxygen, including superoxide anion ( ⁇ 2 ), peroxide (O 2 2 ), hydrogen peroxide (H 2 0 2 ), hydroxyl radical ( ⁇ H) and hydroxyl radical ion (OH ). These molecules may be produced as byproducts during the aerobic respiration or by oxidoreductase enzymes and metal catalyzed oxidation.
  • ROS play a role in immunity and cell signaling, including apoptosis, gene expression, and the activation of cell signaling cascades.
  • excessive ROS production and/or impaired ROS reduction may lead to overload of ROS and oxidative stress.
  • NOX NADPH oxidase
  • COX cyclooxygenases
  • substrate coupled nitric oxide synthetase substrate coupled nitric oxide synthetase
  • the disclosure relates to a series of NADPH oxidase inhibitors, a pharmaceutical composition comprising the same, and a method of inhibiting NADPH oxidase (NOX) activity.
  • a compound according to Formula (I) is provided.
  • the pharmaceutically acceptable salt, hydrate or solvate of this compound are also provided.
  • A is C 6 -C 20 aryl optionally fused with C 1 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl, and A is optionally substituted with one or more C1-C10 alkyl, C 6 -C 2 o aryl, halogen, ORn, C(0)Rn, C(0)0Rn, NR11R12, SO2R11, or S0 2 (0R H ); B is C 1 -C 10 alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl or C 1 -C 20 heterocyclyl and B is optionally substituted with one or more C 1 -C 10 alkyl, C 6 -C 20 aryl, C 1 -C 20 heterocyclyl, halogen, OR21, C(0)R 2i , C(0)0R 2i , NR21R22, SO2R21, or S0 2 (0R 2i ), wherein said
  • n is a single bond or double bond; n is 0 or 1 ; X is N or C; Y is H, OH or N3 ⁇ 4; Z is nil or C(O); R 3 and R 4 independently are nil, H, C 1 -C 10 alkyl or C 6 -C 20 aryl; and R 5 is nil, H or C 1 -C 10 alkyl.
  • a pharmaceutical composition comprises the compound according to Formula I and at least a pharmaceutically acceptable excipient or carrier.
  • a method of inhibiting NADPH oxidase comprises the step of administering to a cell an effective amount of the compound according to Formula I or the pharmaceutical composition comprising the compound according to Formula I and at least a pharmaceutically acceptable excipient or carrier.
  • compositions comprising, “comprising,” “includes,” “including,”“has,”“having,”“contains”,“containing,”“characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.
  • All of the carbon, hydrogen, oxygen, Sulfur, halogen, or nitrogen involved in the groups and compounds according to the present disclosure are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, the hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen) and tritium (T, also known as superheavy hydrogen), the oxygen isotopes include 16 0, 17 0 and 18 0, the sulfur isotopes include 32 S, 33 S, 34 S and 36 S, the nitrogen isotopes include 14 N and 15 N, the fluorine isotopes include 17 F and 19 F, the chlorine isotopes include 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • the carbon isotopes include 12 C, 13 C and 14 C
  • the hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen) and
  • Alkyl means a linear or branched saturated aliphatic hydrocarbyl having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms. Non-limiting examples thereof include methyl, ethyl, n-propyl, isopropyl n-butyl, sec-butyl, t-butyl, isobutyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, octyl, and various branched isomers thereof.
  • Alkenyl means a linear or branched unsaturated aliphatic hydrocarbyl having 1 to 3 carbon-carbon double bonds, and comprising 2 to 20 carbon atoms, preferably 2 to 8.
  • Non limiting examples thereof include vinyl, propen-2-yl, buten2- yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen3-yl, hepten-2-yl, hepten-3- yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and hendecen-3-yl.
  • Alkenyl can also include polyenes such as 1,2 propadienyl and 2,4 hexadienyl.
  • Alkynyl means a linear or branched unsaturated aliphatic hydrocarbyl having 1 to 3 carbon-carbon triple bonds, and comprising 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms.
  • Non limiting examples thereof include ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-2-yl, butyn-3-yl, 3.3-dimethylbutyn-2-yl, pentyn-l-yl, pentyn-2-yl, hexyn-l-yl, heptyn-l-yl, heptyn-3-yl, heptyn-4-yl, octyn-3- yl, nonyn-3-yl, decyn4-yl, hendecyn-3-yl or dodecyn-4-yl.
  • “Alkynyl” can also include moi
  • Alkoxy means -O-alkyl. Non-limiting examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy. This definition applies to the alkoxys used throughout this Description.
  • halogen either alone or in compound words such as“haloalkyl”, or when used in descriptions such as“alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as“alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • Non-limiting examples of“haloalkyl” or“alkyl substituted with halogen” include F 3 C-, ClCH 2 -, CF 3 CH 2 - and CF 3 CCl 2 -.
  • “Aromatic” indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the ring plane, and that (4n + 2) p electrons, where n is a positive integer, are associated with the ring to comply with Huckel’s rule.
  • the term“aromatic ring or ring system” denotes a carbocyclic or heterocyclic ring or ring system in which the ring or at least one ring of the ring system is aromatic.
  • the term“aromatic ring or ring system” is also referred to as“aryl”.
  • “Aryl” might include 6 to 20 carbons as ring member including phenyl, benzyl, naphthyl, and the like.
  • Aryl can also include substituted aryl groups such as tolyl.
  • the term“aromatic heterocyclic ring system” denotes a heterocyclic ring system in which at least one ring of the ring system is aromatic.
  • the term“aromatic heterocyclic ring system” is also referred to as“heteroaryl”. "Heteroaryl” might include 1 to 20 carbons as ring member and might further include at least one heteroatom selected from S, N, and O.
  • Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, a 4- to l2-membered bicyclic or a 10- to 20-membered tricyclic system.
  • the carbocyclic group may have attached bridge rings or spiral rings. Non-limiting examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
  • Heterocyclyl means a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 1 to 8-membered monocyclic, a 4- to l2-membered bicyclic or a 10- to 20- membered tricyclic system, and contains at least one heteroatom selected from N, O or S.
  • the optionally substituted N or S on the ring of a heterocyclic group may be oxidized into various oxidation States.
  • the carbocyclic group may be attached via a heteroatom or a carbon atom, and may have attached bridge rings or spiral rings.
  • Non limiting examples thereof include epoxyethyl, azacyclopropyl, oxzcyclobutyl, azacyclobutyl, l,3-dioxolane, 1 ,4-dioxolane, l,3-dioxane, azacycloheptyl, pyridinyl, furyl, thiophenyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, hexahydropyridinyl, morpholinyl, thiomorpholinyl, l,3-dithia-, dihydrofuryl, dihydropyranyl, dithiacyclopentyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, t
  • the term “optional” or “optionally” means the event or situation modified by this term may but does not certainly happen, including both the case where the event or situation happens and the case not.
  • the term “optionally substituted” refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
  • a heterocyclyl optionally substituted with alkyl means that the alkyl may be present but is not necessarily present, including both the case where the heterocyclyl is substituted with alkyl and the case where the heterocyclyl is not substituted with alkyl.
  • a "pharmaceutically acceptable” component means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • Carrier means a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and characteristics of a given compound.
  • Excipient means an inert substance added into a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples thereof include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluent, a granulating agent, lubricant, binder and disintegrant.
  • the term“effective amount” refers to the amount of each active agent required to confer the desired effect (e.g . inhibiting NADPH oxidase) on the subject, either alone or in combination with one or more other active agents.
  • An effective amount varies, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation.
  • a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
  • stereoisomer refers to an isomer of a molecule having its atoms in a different spatial arrangement, including cis-trans-isomer, enantiomer, and conformer.
  • Compounds of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, racemates, atropisomers and geometric isomers.
  • Stereoisomers are isomers of identical constitution but differing in the arrangement of their atoms in space and include enantiomers, diastereomers, cis- trans isomers (also known as geometric isomers) and atropisomers.
  • Atropisomers result from restricted rotation about single bonds where the rotational barrier is high enough to permit isolation of the isomeric species.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • Embodiments of the present disclosure as described in the Summary of the Invention include those described below.
  • reference to “a compound of Formula I” includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 1 A compound of Formula (I):
  • A is C 6 -C 20 aryl optionally fused with C 1 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl, and A is optionally substituted with one or more C1-C10 alkyl, C 6 -C 2 o aryl, halogen, ORn, C(0)Rn, C(0)ORn, NR11R12, SO2R11, or S0 2 (ORH); B is C 1 -C 10 alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl or C 1 -C 20 heterocyclyl and B is optionally substituted with one or more C1-C10 alkyl, C 6 -C 2 o aryl, C1-C20 heterocyclyl, halogen, OR21, C(0)R 2i , C(0)OR 2 I , NR21R22, SO2R21, or S0 2 (0R 2i ), wherein said C 1 -
  • Embodiment 2 A compound of Formula I, wherein A is C 6 -C 2 o aryl optionally fused with C 1 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl.
  • Embodiment 3 A compound of Formula I, wherein A is C 6 -C 20 aryl optionally fused with C 1 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl, and A is optionally substituted with one or more C 1 -C 10 alkyl, C 6 - C 20 aryl, halogen, ORn, C(0)Rn, C(0)ORn, NR 11 R 12 , SO 2 R 11 , or S0 2 (ORn).
  • Embodiment 4 A compound of Formula I, wherein A is C 6 -C 2 o aryl.
  • Embodiment 5 A compound of Formula I, wherein A is C 6 -C 2 o aryl fused with C 1 -C 20 heterocyclyl.
  • Embodiment 6 A compound of Formula I, wherein A is C 1 -C 20 heteroaryl.
  • Embodiment 7 A compound of Formula I, wherein A is C 1 -C 20 heteroaryl fused with C 1 -C 20 heterocyclyl.
  • Embodiment 8 A compound of Formula I, wherein A is C 6 -C 20 aryl substituted with one or more C 1 -C 10 alkyl, C 6 -C 20 aryl, halogen, ORn, C(0)Rn, C(0)ORn, NR11R12, SO2R11, or S0 2 (ORH).
  • Embodiment 9 A compound of Formula I, wherein A is C 6 -C 2 o aryl fused with C 1 -C 20 heterocyclyl, and further substituted with one or more C 1 -C 10 alkyl, C 6 -C 20 aryl, halogen, ORn, C(0)Rn, C(0)ORn, NR11R12, SO2R11, or S0 2 (ORn).
  • a compound of Formula I wherein A is C 1 -C 20 heteroaryl substituted with one or more C1-C10 alkyl, C 6 -C 2 o aryl, halogen, ORn, C(0)Rn, C(0)ORn, NR 11 R 12 , SO 2 R 11 , or S0 2 (OR I I ).
  • Embodiment 11 A compound of Formula I, wherein A is C 1 -C 20 heteroaryl fused with C 1 -C 20 heterocyclyl, and further substituted with one or more C 1 -C 10 alkyl, C6-C20 aryl, halogen, ORn, C(0)Rn, C(0)ORn, NR11R12, SO2R11, or S02(ORn).
  • Embodiment 12 A compound of Formula I, wherein B is C 1 -C 10 alkyl, C 6 - C20 aryl, C1-C20 heteroaryl or C1-C20 heterocyclyl.
  • Embodiment 13 A compound of Formula I, wherein B is C 1 -C 10 alkyl, C 6 - C20 aryl or C1-C20 heteroaryl.
  • Embodiment 14 A compound of Formula I, wherein B is C 1 -C 10 alkyl, Ci- C 20 heteroaryl or C 1 -C 20 heterocyclyl.
  • Embodiment 15 A compound of Formula I, wherein B is C 1 -C 10 alkyl, C 6 - C 20 aryl or C 1 -C 20 heterocyclyl.
  • Embodiment 16 A compound of Formula I, wherein B is C 1 -C 10 alkyl or C 6 - C20 aryl.
  • Embodiment 17 A compound of Formula I, wherein B is C 1 -C 10 alkyl or Ci- C 20 heteroaryl.
  • Embodiment 18 A compound of Formula I, wherein B is C 1 -C 10 alkyl or Ci-
  • Embodiment 19 A compound of Formula I, wherein B is C 6 -C 20 aryl or Ci- C 20 heteroaryl.
  • Embodiment 20 A compound of Formula I, wherein B is C 6 -C 2 o aryl or Ci- C 20 heterocyclyl.
  • Embodiment 21 A compound of Formula I, wherein B is C 1 -C 20 heteroaryl or C 1 -C 20 heterocyclyl.
  • Embodiment 22 A compound of Formula I, wherein B is C 1 -C 10 alkyl.
  • Embodiment 23 A compound of Formula I, wherein B is C 6 -C 2 o aryl.
  • Embodiment 24 A compound of Formula I, wherein B is C 1 -C 20 heteroaryl.
  • Embodiment 25 A compound of Formula I, wherein B is C 1 -C 20 heterocyclyl.
  • Embodiment 26 A compound of any one of Embodiments 12-25, wherein B is substituted with one or more C1-C10 alkyl, C6-C20 aryl, C1-C20 heterocyclyl, halogen, OR21, C(0)R 2I , C(0)OR 2I , NR21R22, SO2R21 , or S0 2 (0R2i).
  • Embodiment 27 A compound of Embodiment 26, wherein B is substituted with one or more C 1 -C 10 alkyl and said C 1 -C 10 alkyl is substituted with one or more halogen.
  • Embodiment 28 A compound of any one of Embodiments 8-11 and 26-27, wherein Rn, Ri 2 , R21 and R22 independently are H, O, C1-C10 alkyl, or C6-C20 aryl,
  • Embodiment 29 A compound of Embodiment 28, wherein Rn, R12, R21 and R22 independently is C1-C10 alkyl and said C1-C10 alkyl is substituted with one or more halogen.
  • Embodiment 30 A compound of Formula I, wherein n is 0.
  • Embodiment 31 A compound of Formula I, wherein n is 1.
  • Embodiment 32 A compound of Formula I, wherein X is N or C.
  • Embodiment 33 A compound of Formula I, wherein X is N and Y is H, OH or NH 2 .
  • Embodiment 34 A compound of Formula I, wherein X is N and Y is H.
  • Embodiment 35 A compound of Formula I, wherein X is C and Y is H, OH or NH 2 .
  • Embodiment 36 A compound of Formula I, wherein X is C and Y is H.
  • Embodiment 37 A compound of Formula I, wherein X is C and Y is OH.
  • Embodiment 38 A compound of Formula I, wherein X is C and Y is NH 2 .
  • Embodiment 39 A compound of Formula I, wherein Z is nil or C(O)
  • Embodiment 40 A compound of Formula I, wherein Z is nil.
  • Embodiment 41 A compound of Formula I, wherein Z is C(O).
  • Embodiment 42 A compound of Formula I, wherein R3 and R 4 independently are nil, H, C1-C10 alkyl or C6-C20 aryl.
  • Embodiment 43 A compound of Formula I, wherein R 3 is nil and R 4 is nil,
  • Embodiment 44 A compound of Formula I, wherein R 3 is nil and R 4 is nil.
  • Embodiment 45 A compound of Formula I, wherein R 3 is nil and R 4 is H.
  • Embodiment 46 A compound of Formula I, wherein R 3 is nil and R 4 is Ci- Cio alkyl.
  • Embodiment 47 A compound of Formula I, wherein R 3 is nil and R 4 is C 6 - C20 aryl.
  • Embodiment 48 A compound of Formula I, wherein R 3 is H and R 4 is nil,
  • Embodiment 49 A compound of Formula I, wherein R 3 is H and R 4 is nil.
  • Embodiment 50 A compound of Formula I, wherein R 3 is H and R 4 is H.
  • Embodiment 51 A compound of Formula I, wherein R 3 is H and R 4 is Ci- C10 alkyl.
  • Embodiment 52 A compound of Formula I, wherein R 3 is H and R 4 is C 6 - C20 aryl.
  • Embodiment 53 A compound of Formula I, wherein R 3 is C1-C10 alkyl and R 4 is nil, H, C1-C10 alkyl or C6-C20 aryl.
  • Embodiment 54 A compound of Formula I, wherein R 3 is C1-C10 alkyl and
  • R 4 is nil.
  • Embodiment 55 A compound of Formula I, wherein R 3 is C1-C10 alkyl and R 4 is H.
  • Embodiment 56 A compound of Formula I, wherein R 3 is C1-C10 alkyl and R 4 is C1-C10 alkyl.
  • Embodiment 57 A compound of Formula I, wherein R 3 is C1-C10 alkyl and R 4 is C6-C20 aryl.
  • Embodiment 58 A compound of Formula I, wherein R 3 is C6-C20 aryl and R 4 is nil, H, C1-C10 alkyl or C 6 -C 2 o aryl.
  • Embodiment 59 A compound of Formula I, wherein R 3 is C 6 -C 2 o aryl and
  • R 4 is nil.
  • Embodiment 60 A compound of Formula I, wherein R 3 is C6-C20 aryl and R 4 is H.
  • Embodiment 61 A compound of Formula I, wherein R 3 is C 6 -C 2 o aryl and R.4 is Ci-Cio alkyl.
  • Embodiment 62 A compound of Formula I, wherein R 3 is C 6 -C 2 o aryl and R 4 is C 6 -C 2 o aryl.
  • Embodiment 63 A compound of Formula I, wherein R 5 is nil, H or Ci-Cio alkyl.
  • Embodiment 64 A compound of Formula I, wherein R 5 is nil or H.
  • Embodiment 65 A compound of Formula I, wherein R 5 is nil, or Ci-Cio alkyl.
  • Embodiment 66 A compound of Formula I, wherein R 5 is H or Ci-Cio alkyl.
  • Embodiment 67 A compound of Formula I, wherein R 5 is nil.
  • Embodiment 68 A compound of Formula I, wherein R 5 is H.
  • Embodiment 69 A compound of Formula I, wherein R 5 is Ci-Cio alkyl.
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula I but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula I.
  • embodiments of this invention including Embodiments 1-69 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present disclosure.
  • A is C 6 -C 20 aryl optionally fused with C 1 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl, and A is optionally substituted with one or more C 1 -C 10 alkyl, C 6 -C 2 o aryl, halogen, OR 11 , C(0)Rn, C(0)ORn, NR 11 R 12 , SO 2 R 11 , or S0 2 (OR H );
  • B is C 1 -C 10 alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl or C 1 -C 20 heterocyclyl, and B is optionally substituted with one or more C1-C10 alkyl, C 6 -C 2 o aryl, C1-C20 heterocyclyl, halogen, OR21, C(0)R 2i , C(0)OR 2i , NR21R22, SO2R21, or S0 2 (0R 2I ), wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen;
  • R 11 , R 12 , R 21 and R 22 independently are H, O, C 1 -C 10 alkyl, or C 6 -C 20 aryl, wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen; is a single bond or double bond; n is 0 or 1;
  • X is N or C
  • Y is H, OH or NH 2 ;
  • Z is nil or C(O);
  • R 3 and R 4 independently are nil, H, Ci-Cio alkyl or C 6 -C 20 aryl; and R 5 is nil, H or Ci -Ci 0 alkyl.
  • Embodiment B A compound of Embodiment A represented by Formula
  • A is C 6 -C 2 o aryl optionally fused with C1-C20 heterocyclyl, or C1-C20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl, and A is optionally substituted with one or more C 1 -C 10 alkyl, C 6 -C 20 aryl, halogen, ORn, C(0)Rn, C(0)0Rn,
  • B is C 1 -C 10 alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl or C 1 -C 20 heterocyclyl and is optionally substituted with one or more C 1 -C 10 alkyl, C 6 -C 2 o aryl, C 1 -C 20 heterocyclyl, halogen, OR21, C(0)R2i, C(0)0R2i, NR21R22, SO2R21, or S0 2 (0R 2I ), wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen;
  • Rn, R12, R21 and R22 independently are H, O, C1-C10 alkyl, or C6-C20 aryl, wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen;
  • Y is OH or NH 2 ; Z is nil or C(O); and
  • R 5 is nil, H, or Ci -Ci 0 alkyl.
  • Embodiment C A compound of Embodiment A represented by Formula (III)
  • A is C 6 -C 20 aryl optionally fused with C 1 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl optionally fused with C 1 -C 20 heterocyclyl, and A is optionally substituted with one or more C 1 -C 10 alkyl, C 6 -C 2 o aryl, halogen, ORn, C(0)Rn, C(0)0Rn, NR 11 R 12 , SO 2 R 11 , or S0 2 (0R H );
  • B is C 1 -C 10 alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl or C 1 -C 20 heterocyclyl, and B is optionally substituted with one or more C1-C10 alkyl, C 6 -C 2 o aryl, C1-C20 heterocyclyl, halogen, OR21, C(0)R 2i , C(0)0R 2i , NR21R22, SO2R21, or S0 2 (0R 2I ), wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen;
  • Rn, R12, R21 and R22 independently are H, O, C1-C10 alkyl, or C 6 -C 2 o aryl, wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen;
  • Z is nil or C(O); and each R 3 and R 4 independently is nil, H, C 1 -C 10 alkyl or C 6 -C 20 aryl.
  • Embodiment D A compound of any one of Embodiments A-C wherein
  • A is substituted or unsubstituted C 6 -C 20 aryl or C 6 -C 20 aryl fused with C 1 -C 20 heterocyclyl.
  • Embodiment E A compound of any one of Embodiments A-D wherein
  • A is phenyl group substituted with one or more methoxy group, (dimethylamide) phenyl group, Br, ORn, or C(0)ORn, wherein Rn is H, O, C 1 -C 10 alkyl, or C 6 - C 20 aryl, wherein said C 1 -C 10 alkyl is optionally substituted with one or more halogen.
  • Embodiment F A compound of any one of Embodiments A-C wherein
  • A is substituted or unsubstituted C 1 -C 20 heteroaryl having at least one heteroatom selected from S, N, and O.
  • Embodiment G A compound of Embodiment F. wherein
  • A is pyrroline, furan, thiophene, pyridine, pyran, or thiopyran.
  • Embodiment H A compound of any one of Embodiments A-D wherein A is substituted or unsubstituted C 6 -C 2 o aryl fused with C1-C20 heterocyclyl having at least one heteroatom selected from S, N, and O.
  • Embodiment I A compound of Embodiment H wherein
  • A is l,3-benzodioxole, indoline, indole, indazole, benzofuran, benzo[c]thiophene, benzo[£]thiophene, 1 ,2-benzisoxazole, l,2-benzisothiazole, 2,l-benzisothiazole, benzoxazole, or benzthiazole.
  • Embodiment J A compound of any one of Embodiments A-I wherein
  • B is substituted or unsubstituted C1-C10 alkyl.
  • Embodiment K A compound of Embodiment J wherein
  • B is methyl, ethyl, n-propyl, i-propyl or tert- butyl group.
  • Embodiment L A compound of any one of Embodiments A-I wherein
  • B is substituted or unsubstituted C6-C20 aryl.
  • Embodiment M A compound of Embodiment L wherein
  • B is a phenyl group substituted with one or more methyl, CF3, halogen, pyrrolidine, OR21, C(0)R2i, NR21R22, or SO2R21.
  • Embodiment N A compound of Embodiment M wherein
  • R21 is H, O, methyl, ethyl, n-propyl, or CF 3 ; and R22 is H or O.
  • Embodiment O A compound of any one of Embodiments A-I wherein
  • B is substituted or unsubstituted C1-C20 heteroaryl.
  • Embodiment R A compound of Embodiment O wherein
  • B is pyrroline, furan, thiophene, pyridine, pyran, or thiopyran.
  • Embodiment Q A compound of any one of Embodiments A-P wherein n is 0.
  • Embodiment R A compound of any one of Embodiments A-Q wherein
  • Embodiment S A compound of any one of Embodiments A-R wherein Y is H, OH or NH 2 .
  • Embodiment T A compound of any one of Embodiments A-Q wherein X is N.
  • Embodiment U A compound of Embodiment T wherein Y is H or NH 2 .
  • Embodiment V A compound of any one of Embodiments A-U wherein Z is nil or C(O).
  • Embodiment W A compound of Embodiments A-P wherein n is 1.
  • Embodiment X A compound of Embodiment W wherein
  • R 3 and R 4 independently are nil, H, methyl, ethyl, n-propyl, i-propyl, tert- butyl, phenyl, benzyl, or naphthyl.
  • Embodiment Y A compound of Embodiment A wherein
  • R 5 is nil, H, methyl, ethyl, n-propyl, i-propyl or /e/V-butyl group.
  • compositions comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and any combinations thereof.
  • the composition can be formulated to any form of formulation that is considered to be safe, effective, and convenient for use.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable component as defined in the previous paragraphs.
  • a usable pharmaceutically acceptable salt, carrier, or excipient are disclosed in various references including Handbook of Pharmaceuticals Excipients edited by Raymond C Rowe, Paul J Sheskey, and Marian E Quinn.
  • said pharmaceutically acceptable carrier or excipient can be selected from the group consisting of inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents and oils. Said compositions optionally further comprising at least one additional biologically active compound or agent.
  • said composition could be a pharmaceutical composition.
  • the pharmaceutical composition might comprise but not limited to a single unit dose of the active ingredient (for instance, the compound of the present disclosure).
  • a dose unit can be in the form of a discrete article such as but not limited to a tablet or capsule, or can be a measurable volume of a solution, suspension or the like containing a unit dose of the active ingredient.
  • unit dose herein refers to an amount of active ingredient intended for a single but not limited to oral, intravenous, intramuscular, cutaneous, subcutaneous, intrathecal, transdermal, implantation, sublingual, buccal, rectal, vaginal, ocular, otic, nasal, inhalation, or nebulization administration to a subject for inhibiting NADPH oxidase (NOX).
  • NOX NADPH oxidase
  • the inhibitory to NOX may require periodic administration of unit doses of the compound of the present disclosure, for example one unit dose two or more times a day, one unit dose with each meal, one unit dose every four hours or other interval, or only one unit dose per day.
  • compositions for inhibiting NADPH oxidase (NOX) activity comprising a compound of any of the preceding Embodiments, as well as any other embodiments described herein, and any combinations thereof, and at least one of a pharmaceutically acceptable excipient or carrier selected from the group consisting of inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils, said compositions optionally further comprising at least one additional biologically active compound or agent.
  • a pharmaceutically acceptable excipient or carrier selected from the group consisting of inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils
  • Embodiments of the invention further include methods for inhibiting NADPH oxidase (NOX) activity in cell comprising administering to the cell an effective amount of the compound or the pharmaceutical composition of any of the preceding Embodiments ( e.g ., as a composition described herein).
  • NOX NADPH oxidase
  • Step 2 Preparation of 3-hydroxy-6, 7-dim ethoxy-2-(4-methoxyphenyl) quinolin-4(lH)-one 2,2,2-trifluoroacetate
  • Step 1 A Preparation of 2-bromo-l-(2-ethoxyphenyl) ethan-l-one
  • Step 1A Preparation of 2-bromo-l-(2-(methylsulfonyl)phenyl) ethan- 1-one
  • Step 1 Preparation of bis(2-(4-methoxyphenyl)-2-oxoethyl) 2- aminoterephthalate
  • Step 2 Preparation of 2-(4-methoxyphenyl)-2-oxoethyl 3-hydroxy-2-(4- methoxyphenyl)-4-oxo-l,4-dihydroquinoline-7-carboxylate 2,2,2-trifluoroacetate
  • Step 3 Preparation of 3-hydroxy-2-(4-methoxyphenyl)-4-oxo-l,4- dihydroquinoline-7-carboxylic acid
  • a solution of sodium ethoxide (Na, 2 mmol in dry EtOH, 5 mL) was add a suspension of 2,3-dihydro-2,3-dioxo-lH-indole (0.l7g, 1.0 mmol) and 2-bromo-2 methoxy acetophenone (0.23g, 1.0 mmol) in dry EtOH (5 mL).
  • the mixture was maintained at 0-5°C for 2 hr.
  • the reaction mixture was allowed to warm up to room temperature and stirred for l8h.
  • the mixture was acidified with 2N HCl (aq.) and extracted with EA.
  • the organic phase was dried with MgS0 4 and concentrated under reduced pressure to give the crude mixture.
  • Step 2 Preparation of 2-(2-chlorophenyl)-7,8-dimethoxy-3,4-dihydro- 5H-benzo[e][l,4] diazepin-5-one and 3-amino-2-(2-chlorophenyl)-6,7- dimethoxyquinolin-4(lH)-one
  • Step 1 Preparation of (3-hydroxy-6,7-dimethoxy-2-(2-(trifhioromethyl) phenyl) quinolin-4(lH)-one
  • Step 2A Preparation of 3-hydroxy-6,7-dimethoxy-2-(2- (trifluoromethyl)phenyl) quinolin-4(lH)-one hydrochloride
  • Step 2B Preparation of 3-hydroxy-6,7-dimethoxy-2-(2- (trifluoromethyl)phenyl)quinolin-4(lH)-one acetate
  • Step 2C Preparation of 3-hydroxy-6, 7-dim ethoxy-2-(2-
  • active agent includes the pharmaceutically acceptable salts of the compound.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like;
  • pharmaceutically acceptable salts are formed with malic acid.
  • pharmaceutically acceptable salts are formed with hydrochloric acid.
  • Active agents used to prepare compositions for the present disclosure may alternatively be in the form of a pharmaceutically acceptable free base of active agent. Because the free base of the compound is less soluble than the salt, free base compositions are employed to provide more sustained release of active agent to the target area. Active agent present in the target area which has not gone into solution is not available to induce a physiological response, but serves as a depot of bioavailable drug which gradually goes into solution.
  • BIOLOGICAL EXAMPLES OF THE INVENTION Another aspect of the invention relates to methods of inhibiting NADPH oxidase (NOX) in cell, comprising the step of administering to the cell an effective amount of the compound or the pharmaceutical composition according to embodiments of the present application.
  • NOX NADPH oxidase
  • samples with NOX activity include enzymes; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; biological samples such as extracts of cells, particularly recombinant cells expressing NOX; and the like. Samples can be contained in any medium including water and organic solventYwater mixtures.
  • the NOX inhibiting activity of a compound of the present disclosure after use of the compound or the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semiquantitative methods of determining such activity are all contemplated. Typically one of the methods described below are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • the NOX inhibiting activity of a compound or a composition according to the present application can be measured using standard screening protocols that are known.
  • the NOX inhibiting activity of a compound or a composition can be measured using the following general protocols.
  • NOX1 HT29 cell-based assay [0198]
  • HT29 cells were cultured in T75 flask (Corning) and when 70-80% confluence was reached, cells were trypsinized, harvested in HBSS and counted. 1 -2 x 10 5 cells were dispensed into individual wells in 70m1 final volume (96-well plates, white Corning). Cells were treated for 30-60mins at 37°C with 10m1 of GKT137831, DMSO and test compounds from their respective assay plates. This will correspond to a final concentration of 100 nM, 1000 nM GKT137831 or test compounds, and 0.1% DMSO. 20 pL of a mixture containing 100 mM luminol plus 0.4 units of HRP (final concentration) was added.
  • Luminescence was quantified using a SpectraMax i3 Multiplate reader (Molecular Devices, Sunnyvale, CA, USA). As designed, compounds that inhibit NOX1 activity will reduce cellular ROS production, leading to reduced probe-ROS interactions and reduced well luminescence. Compounds were tested in duplicate at a concentration of 100hM and lOOOnM. DMSO and GKT137831 wells were applied as negative and positive controls, and the activities measured were set to 0% and 100%, respectively.
  • NOX2 HL60 cell-based assay [0200]
  • HL-60 cells rich in N0X2 expression, was stimulated to undergo oxidative burst by phorbol myristate acetate (PMA).
  • PMA phorbol myristate acetate
  • the ROS produced during this process was measured using the 0 2 -specitic chemiluminescent probe L012. L012 was added to
  • DMSO-differentiated HL-60 cell suspensions to a final concentration of 100 mM. Then, 80 mT aliquots of cell suspension (2.5 X 10 5 cells) were transferred to individual wells of a 96- well plate. Test compounds were directly added to the wells at the specified concentrations. Following a 30-60 mins incubation at 37°C in the dark, the oxidative burst was initiated by the addition of 10 ng/mL PMA, and the chemiluminescence signal was recorded every 5 min over a period of 60 mins in a SpectraMax i3 Multiplate reader (Molecular Devices, Sunnyvale, CA, USA).
  • NOX4 HEK293 overexpression cell-based assay [0202]
  • Extracellular H2O2 measurement using AmplexTM Red Hydrogen Peroxide/Peroxidase Assay Kit (Catalog number: A22188; Invitrogen, Carlsbad, CA, USA) was used to detect extracellular H2O2 release by HEK293 cells stably overexpressing NOX4.
  • NOX4 clonal cells in log-phase growth were trypsinized, washed, and dispersed thoroughly. Following trypsinization, the cells (3 xlO 4 ) were resuspended in 100 pL of IX Krebs-Ringer phosphate glucose (KRPG) buffer containing various concentrations of GKT137831 or test compounds and incubated at 37 °C for 30 min.
  • KRPG IX Krebs-Ringer phosphate glucose
  • A indicates that the percent of inhibition of NOX by the compounds is larger than or equals to 80%; B indicates that the percent of inhibition of NOX by the compounds ranges from 50% to 79%; C indicates that the percent of inhibition of NOX by the compounds ranges from 20% to 49%; and D indicates that the percent of inhibition of NOX by the compounds is smaller than or equals to 19%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un composé de formule I, ou un isomère géométrique, un énantiomère, un diastéréoisomère, un racémate, un atropisomère, un sel pharmaceutiquement acceptable, un promédicament ou un solvate de celui-ci. La présente invention concerne en outre une composition comprenant le composé de formule (I). Le composé et la composition de l'invention peuvent être utilisés pour inhiber l'activité de NADPH oxydase.
PCT/US2019/038140 2018-06-21 2019-06-20 Inhibiteurs de la nadph oxydase, composition pharmaceutique les comprenant et application de ceux-ci WO2019246343A1 (fr)

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